PROJECT SUMMARY/ABSTRACT Dr. Zhenghui Gordon Jiang, a physician in Gastroenterology at Beth Israel Deaconess Medical Center (BIDMC) and an Instructor in Medicine at Harvard Medical School, has a career goal to establish himself as an independent physician-scientist in the field of nonalcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), and liver fibrosis. In addition to running a NAFLD specialty clinic, Dr. Jiang currently spends 70% of his time in translational research supported by the Department of Medicine at BIDMC and external funding such as the CTRA award from the Liver Research Foundation. A K08 award will further provide the protected time and support necessary for him to accomplish the following goals in NAFLD research: 1) define the mechanism by which adenosine deaminase 2 (ADA2) modulates macrophage (M) phenotype; 2) establish the impact of ADA2 on inflammation and fibrosis, and 3) test the associations of circulating ADA2 activity with insulin resistance, inflammation and liver fibrosis in NAFLD. Drs. Simon Robson and Kenneth Mukamal are complementary mentors on mechanistic and translational aspects of this project. Dr. Jiang has also identified a panel of advisors and assembled a group of collaborators. Drs. Barbara Wegiel and Yury Popov at BIDMC will provide guidance on M and fibrosis research respectively. Dr. Majken Jensen at Harvard Chan School of Public Health will advise on the use of large clinical database and stored samples from the Multi-Ethnic Study of Atherosclerosis (MESA). A proportion of NAFLD patients will develop inflammation and progressive fibrosis ultimately leading to cirrhosis and liver cancer. The mechanism behind this difference in the natural history of NAFLD patients is unclear. Recent work has suggested that the activity of ADA2 in the blood, an ecto-enzyme that catalyzes the conversion of adenosine to inosine, correlate with the histological stage of liver fibrosis in NAFLD patients. Furthermore, M in the portal area express ADA2 and accumulate in the setting of steatohepatitis and fibrosis. Our preliminary studies point to the involvement of a novel ADA2 and adenosinergic pathway in regulating inflammation and fibrosis in NAFLD. The central hypothesis is that ADA2 modulates M phenotype and influences liver fibrosis in NAFLD. Dr. Jiang further postulates that ADA2 released by infiltrative M activates other immune cells in the liver, including Kupffer cells, and perpetuates liver fibrosis and hepatic insulin resistance. The hypothesis will be tested by pursuing two specific aims: Aim 1. To define the ADA2 pathway in modulating M by elucidating the immune phenotype associated with ADA2 production, and the mechanism and impact of ADA2 action in vitro and in NAFLD. Aim 2. To define the relationship of circulating ADA2 activity with inflammation, insulin resistance and liver fibrosis among individuals with NAFLD in the Multi-Ethnic Study of Atherosclerosis. The proposed studies will build upon emerging data to further define the ADA2/adenosinergic pathways relevant to liver inflammation and fibrosis in NAFLD, to develop Dr. Jiang's career toward an independent physician- scientist, and to generate the necessary preliminary data to obtain R01-funding at the end of this award.